Natural Killer (NK) cells are an important part of innate immune defense, with a capacity to recognize virus infected and transformed cells. In contrast to T and B cells, they do not need to clonally expand, but can act directly through cytotoxicity and secretion of both cytokines and chemokines. The physiological role of NK cells during HIV infection remains unclear, although they have been shown to inhibit HIV replication in vitro, partially by the release of chemokines. NK cell function and number has been reported to be impaired in HIV-infected individuals, with partial restoration after suppression of the viral load by HAART. Moreover, expression of certain inhibitory and activating NK cell receptors correlate with viral load and/or progression to AIDS in HIV-infected patients. The first aim of this grant application is focused on the relationship between the frequency, number, and function of NK cells early in HIV infection and the level of plasma viremia post seroconversion (virological set point), the temporal kinetics of the NK cell response in relationship to plasma HIV viral load in early HIV infection, and the effect of HIV viremia on NK cell receptor expression. The second aim is to determine how the time of initiation of treatment with highly active antiretroviral drug therapy (HAART) and how interleukin-2 therapy impact the frequency and function of NK cells in HIV-infected individuals. These studies will use samples taken from a cohort of HIV-infected subjects enrolled in the UCSF "Options Project," run by co-investigator Dr. F. Hecht. The studies proposed in this grant will have direct relevance for understanding the physiological role of NK cells in the pathogenesis of HIV infection, and how antiretroviral treatments and IL-2 therapy affect NK cell functions in HIV-infected subjects.